Our previous studies of the role of natural killer (NK) cells in atherosclerosis were performed in Low Density Lipoprotein (LDL) receptor-deficient (LDLr-/-) mice that were crossed with the severely NK cell-deficient Beige (bg) mutant mice. In these studies we observed striking disease differences between double mutant LDLr-/-bg mice and LDLr-/- mice. The disease in the LDLr-/-bg mice was more severe and lesion morphologies were distinct. Lesion macrophages (Mphi) in the LDLr-/-bg mice were fewer and were confined to the narrow luminal surface of the intima. Large necrotic cores were absent. Instead, smooth muscle cells (SMC) occupied a larger portion of the intima that was rich in collagen. This competing grant renewal describes studies to identify the tissue specificity and the mechanisms underlying these disease differences between LDLr-/- and LDLr-/-bg mice. Because the bg mutation is expressed in all cells, bone marrow transplantation will be used in Aim 1 to identify if bone marrow-derived and/or non-bone marrow-derived cells are responsible for the disease differences. The studies will make use of green fluorescent protein (GFP)-expressing mice to distinguish tissue origin. Aim 2 will verify that the bg disease phenotype is not unique to LDLr-/- mice by confirming that double mutant apoE-/-bg mice also express a more severe disease and distinct morphology. The third Aim will identify mechanisms responsible for the expression of the bg atherosclerosis phenotype. These studies will reveal the role of lysosomal trafficking defects of the mutant bg protein in cellular cytokine expression; cellular adhesion and migration; cellular survival, proliferation and apoptosis as well as cellular cholesterol metabolism. The power of comparing LDLr- /-bg with LDLr-/- mice will allow us to focus on those cellular activities that are physiologically relevant and participate in vivo in a very complex and still poorly understood disease process.